PSMS-IN-INFLAMMATION · Imaging Innate Immunity of Staphylococcal Infections
FP7 — People (Marie Curie Actions)
- Duration
- 2014-04-09 → 2017-04-08
- EU contribution
- €259,583
- Participants
- 1
- Scheme
- MC-IOF
Lines connect the coordinator with its partners.
Results in brief
Imaging Innate Immunity of Staphylococcal Infections
This study was designed to dissect the role of Staphylococcal phenol soluble modulins (PSMs) in bacterial pathogenesis and visualize how Staphylococcus aureus modulate host immunology in vivo. Dr. Surewaard has approached this research project by learning cutting-edge real-time in vivo imaging techniques such as Spinning-disk confocal intravital microscopy (SDIVM) and Multi photon IVM (MPIVM), but also made use of standard multidisciplinary methodologies in: microbiology, histopathology, immunology and biochemistry. These techniques were also applied to study a number of serous pathogens including Streptococcus pneumonia, Pseudomonas aeruginosa and Escherichia coli Surewaard has learned and gained extensive experience in intravital microscopy to study bacterial pathogenesis in experimental animal models. He has developed various fluorescent reporter strains in clinical important pathogenic bacterial strains. The applicant gained experience in Immunohistochemistry to determine in which cellular compartment Staphylococcus aureus is able to replicate and confirmed this data using electron microscopy. Using high resolution Z-stack images and newly developed replication reporter strains surewaard could show that Staphylococcus aureus replicates and forms intracellular micro-colonies of up to 80 bacteria inside Kupffer cells. In addition newly developed antibiotics were able to target this intracellular reservoir in Kupffer cells and this result was later published in the Journal of Experimental Medicine. In addition Surewaard and Z. Zeng have discovered the mechanism how Gram-positive bacteria a captured by Kupffer cells. Kupffer cells express Crig, however unlike previously thought this receptor does not recognize complement but it recognizes Lipoteichoic acid in the cell wall from Gram-positive bacteria. This new mechanism of bacterial clearance was published in Cell Host and Microbes. In addition collaborations have been established with the pharmaceutical company Medimmune to address the mechanism of action of bi-specific antibodies that work against intracellular virulence factors that high potency in generating new therapeutics for diseases of the bacteria Pseudomonas aeruginosa and Staphylococcus aureus. This data was published last year in the high ranking Journal of Clinical investigation. The data generated by this study are currently accepted for publication high ranking biomedical research journals; Journal of Experimental Medicine, Cell Host and Microbes and Journal of clinical investigations. By publishing in this data many scientist in the field of Infectious disease, immunology and microbiology will have access to it. Furthermore we identified a clinical problem that Methicillin-resistant Staphylococcus aureus (MRSA) actually thrives intracellularly. The pathogen survives and grows inside Kupffer cells and ultimately escapes to colonize other tissues. Based on these findings, a simple, inexpensive and rational way to target and eradicate the pathogen was further uncovered. This immunotherapeutic approach could help treat patients with MRSA bacteremia by increasing effectiveness of antibiotics and decreasing the length of administration. Following these publications we were approached by the Centre of Drug Research and Development (CDRD) based in Vancouver to translating our work into novel therapeutics and I will collaborate extensively the CDRD.
Data: CORDIS, © European Union
Project objective
Staphylococcus aureus community-acquired (CA)-MRSA strains are highly virulent and can cause infections in otherwise healthy individuals and are a leading cause of death worldwide. Innate immunity is our primary defense against invading staphylococci. Blood-neutrophils migrate to the site of infection where they, in concert with the complement system, engulf and kill bacteria in a process called phagocytosis. Especially CA-MRSA strains seem to be very efficient in circumventing this neutrophil killing. Interestingly, only a relative small number of virulence factors have been associated with CA-MRSA, one of which are the phenol soluble modulins (PSMs). In vivo models of experimental infection with PSM-mutants have shown a critical role for PSMs in skin and soft tissue infections. PSMs are small alpha-helical peptides which have two distinct functions on the immune system, in vitro PSMs can attract neutrophils in the nanomolar range, whereas in the micromolar range they are cytolytic for neutrophils. Recent publications suggests that these two functions complement each other for full staphylococcal virulence, although it seems counter-intuitive for S. aureus to actively attract its mortal enemy: the neutrophil. To make matters even more complicated PSMs are functionally inactivated by host serum lipoproteins, most efficiently by high density lipoprotein (HDL). The goal of this research proposal is to determine the mechanism of action for PSMs in staphylococcal disease. To this end, I will use genomic and proteomic approaches combined with cutting edge in vivo spinning-disk confocal microscopy, to dissect the functions of PSMs in host-staphylococcal interactions in; 1) neutrophil recruitment, 2) neutrophil lysis 3) HDL neutralization and liver pathology, 4) Evasion of PSM-recognition by FLIPR-L
Original text from CORDIS.
Participants
- UNIVERSITAIR MEDISCH CENTRUM UTRECHT · UtrechtCoordinatorNetherlands
Links
Data: CORDIS, © European Union